Isohexides such as isosorbide, isomannide and isoidide (sometimes referred to as dianhydrohexitols or anhydrosugar alcohols) have been of considerable commercial interest for a number of years. Isosorbide in particular is currently used to a limited extent as a starting material for isosorbide mononitrate and dinitrate, vasodilators used for treating angina pectoris, congestive heart failure and in other similar contexts, but isosorbide and to a lesser extent the other isohexides have long been considered as having the potential for widespread use as biobased monomers, surfactants and other commodity scale, non-pharmaceutical applications. For example, in relation to the large, commodity scale polymer systems in use today, efforts have been made over a number of years to use isosorbide in the manufacture of polyurethanes, polyesters, polycarbonates and polyamides.
Unfortunately, however, it has proven very difficult to make isosorbide in the requisite purity for such polymeric applications (these uniformly require very high purity materials) at any reasonable scale, much less to make isosorbide in the requisite high purity at a reasonable scale and with sustainable economics in relation to the petrochemically-derived materials which have been conventionally used in these applications.
According to Fuertes in U.S. Pat. No. 8,008,477 (“Fuertes”), in fact, for not only polymeric applications but for the majority of the contemplated applications of isosorbide and other internal dehydration products of hydrogenated sugars, in particular, the other isohexides, it is generally required to apply a purification treatment to the compositions resulting directly from the actual dehydration step. This is in particular because any hydrogenated sugar or sugar alcohol subjected to such a step (for example sorbitol) is likely to be converted at least in part to various other coproducts. Fuertes lists these various other coproducts as including, for example: isomers of the said desired product, for example, isomers of isosorbide such as isomannide and isoidide; products which are less dehydrated than the desired product or than its isomers, for example, sorbitans, mannitans or iditans (some of which are terminal products themselves which do not further undergo dehydration); derivatives resulting from the oxidation or more generally from the degradation of the abovementioned products, it being possible for these derivatives to include, for example, when the desired product is isosorbide, coproducts such as deoxymonoanhydrohexitols, monoanhydropentitols, monoanhydrotetritols, anhydrohexoses, hydroxymethylfurfural, or glycerin; derivatives resulting from the polymerization of the abovementioned products; and/or “highly coloured species of a poorly defined nature”.
Fuertes observes that, in general, all or some of the various categories of coproducts or impurities mentioned are unavoidably generated to a greater or lesser degree during the actual step of dehydration of the hydrogenated sugar, regardless of the dehydration conditions and of the precautions taken, for example, regardless of the acid catalyst used (whether inorganic acid, organic acid, cationic resin, and the like), the quantity of water or of organic solvent(s) in the initial reaction medium, or of the purity of the hydrogenated sugar, for example sorbitol, composition used as raw material.
Fuertes observes that various technologies had been recommended for obtaining isosorbide of a higher purity given these realities, whether by altering the manner in which the sorbitol dehydration is carried out and/or by applying one or more purification treatments on the crude isosorbide product.
The art discussed by Fuertes includes CA 1178288, which recommends at page 14, lines 3-8 to carry out the dehydration under an inert gaseous atmosphere in order to avoid oxidation reactions, in particular when relatively high temperatures and long reaction times are envisaged.
U.S. Pat. No. 4,861,513 describes a sorbitol dehydration reaction carried out simultaneously in the presence of an inert gas (nitrogen) and a reducing agent (sodium hypophosphite) for the preparation of particular mixtures of polyols, which have a low content (10 to 26%) of isosorbide.
For its part, GB 613,444 describes the production, by sorbitol dehydration in a water/xylene medium, of an isosorbide composition which is then subjected to a treatment of distillation and then of recrystallization from an alcohol/ether mixture.
A purification treatment combining distillation and recrystallization from a lower aliphatic alcohol (ethanol, methanol) was recommended in WO 00/14081. This document moreover indicates that, in the case where distillation is the only purification step contemplated, it is advantageous to carry out the said step in the presence of sodium borohydride.
Fuertes observes in discussing WO 00/14081 that other authors had also recommended that the distillation step be carried out in the presence of a boron-containing compound, in particular of boric acid or of an anionic resin previously charged with borate ions, as described in U.S. Pat. No. 3,160,641.
U.S. Pat. No. 4,408,061 and EP 323,994 are similar in describing the use of particular dehydration catalysts (gaseous hydrogen halide and liquid hydrogen fluoride, respectively), advantageously combined with carboxylic acids as co-catalysts followed by the distillation of the crude isosorbide or isomannide compositions thus obtained.
U.S. Pat. No. 4,564,692 is described by Fuertes as mentioning, without giving any details, prepurification on “ion exchangers and/or activated charcoal” of isosorbide or isomannide compositions followed, after concentration by evaporation and seeding of crystals of the desired isohexide, by crystallization thereof from water.
EP 380,402 is summarized as describing the dehydration of hydrogenated sugars in the presence of hydrogen under pressure and of particular catalysts based on a combination between copper and a noble metal of Group VIII or gold. These conditions are presented as making it possible to significantly reduce the formation of impurities of a polymeric nature during the actual dehydration step.
EP 915,091 is mentioned as referencing the possibility of further advantageously reducing the genesis of such undesirable polymers, by using acid-stable hydrogenation catalysts during the dehydration step.
U.S. Pat. No. 7,122,661, commonly assigned with U.S. Pat. No. 8,008,477 to Fuertes and naming Fuertes as a co-inventor, describes a process for obtaining isohexide compositions of 99.5% or greater purity and improved storage stability, without necessarily involving a comparatively costly and low yielding post-distillation crystallization step from a solvent medium, through using an ion-exchange step followed by a decolorization treatment step. More particularly, a distilled isohexide composition is described as subjected to treatment with at least one ion-exchange means, which can be a mixed bed of anionic resin(s) and cationic resin(s) or a succession of cationic resin(s) and anionic resin(s), followed by treatment with at least one “decolorizing means”. The decolorizing means can be activated charcoal in granular or pulverulent form. In certain embodiments, a second treatment with the decolorizing means is contemplated before the ion-exchange treatment step. Improved stability isosorbide compositions were said to be produced by the process, though the same steps—ion-exchange treatment followed by decolorizing means treatment—were surprisingly said to result in a destabilizing effect when performed in the reverse order.
“Stability” as expressed in the '661 patent referred to the stability of a composition over time in terms of variation of the pH, the conductivity and/or the content of certain impurities, formic acid and ionic species generally being specifically mentioned as possible promoters or indicators of instability not recognized in the listed prior art, col. 5, lines 13-22.
Fuertes concludes his review of the art in U.S. Pat. No. 8,008,477 by observing that even if the prior art methods successfully provided an isosorbide product of the required purity—whether by reducing byproduct formation in the dehydration step and/or by post-dehydration purification measures—nevertheless, the purified compositions thus obtained would degrade over time under conventional conditions of storage temperature, i.e., generally between 0 and 40° C. Specifically, Fuertes reported that the stability of an isohexide composition is “not necessarily correlated” with its purity, and preparation in an inert atmosphere and/or in the presence of sodium borohydride in the dehydration or in the distillation step likewise did not materially improve the stability of these compositions, col. 3, lines 58-67. Rather, “only” the use of specific stabilizing agents in nongaseous form and after the distillation step was helpful for improving the storage stability of isohexide compositions at ambient and moderate temperatures, col. 4, lines 1-14. Suitable “stabilizing agents” are chosen from the group comprising reducing agents, antioxidants, oxygen scavengers, light stabilizers, anti-acid agents, metal-deactivating agents and mixtures of at least any two of such materials, col. 4, lines 48-53. In certain embodiments, an optional further “purification step” was taught following the distillation, an example being the use of both ion exchange and decolorizing means of the type described in the earlier '661 patent.
The '477 patent for its part also defines a “stable composition” more precisely than the earlier, commonly-assigned '661 patent. A “stable composition” in the '477 patent was understood to mean a “composition which, when stored in a noninert atmosphere for a period of at least one month and at a temperature of 40 degrees Celsius, has both a formic acid content of less than 5 ppm and an overall content of monoanhydrohexoses of less than 50 ppm, expressed on a dry weight basis relative to the dry weight of the composition as a whole.
While Fuertes thus aptly describes the challenges faced by those skilled in the art in producing an isosorbide product of the needed purity and further appreciates the additional challenge of the tendency of even high purity isosorbide products to degrade over time under conventional storage conditions, yet as documented in the prior related WO'347, WO'351 and WO'356 applications, nevertheless Fuertes as well fails to fully appreciate the complexity of the dehydration chemistry at work in the process of converting sugar alcohols to their twice-dehydrated products, and how readily undesirable byproducts are formed which will lead to the development of color in a finished, purified isohexide product over time under ordinary storage conditions.